Pharmaceutical Compositions of Protac Compounds and Uses Thereof

This application is a division of U.S. application Ser. No. 18/343,324 filed on Jun. 28, 2023, which is a continuation of PCT application No. PCT/CN2023/083796, filed on Mar. 24, 2023, which claims the benefit of patent application Nos. PCT/CN2022/083105, filed on Mar. 25, 2022, and PCT/CN2023/079057, filed on Mar. 1, 2023, each of which is hereby incorporated by reference in its entirety.

The present invention belongs to the pharmaceutical field, and specifically relates to pharmaceutical compositions, and their preparation method and use.

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). This modality has emerged as an orthogonal approach to the use of small-molecule inhibitors for knocking down classic targets and disease-related proteins classified, until now, as “undruggable.” However, PROTACs are often affected by poor cellular permeability due to their high molecular weight (MW) and large exposed polar surface area (PSA).

ARV-110, a PROTAC® protein degrader that targets the androgen receptor (AR). ARV-110 is developed by Arvinas for the potential treatment of men with metastatic castration resistant prostate cancer (mCRPC) and who have progressed on existing therapies. Its molecular weight is 812.29 and its calculated log P is about 4.18. It is very hard to dissolve in the aqueous solution and it is reported that it should be taken with food.

ARV-471, a PROTAC® protein degrader that targets the estrogen receptor (ER). ARV-471 is developed by Arvinas for the potential treatment of women with locally advanced or metastatic estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2−) breast cancer. Its molecular weight is 723.92 and its calculated log P is about 4-6. It is very hard to dissolve in the aqueous solution and it is reported that it should be taken with food in clinic study.

Poor water solubility and very low oral absorption are the bottlenecks to develop RPOTAC molecules for in vivo applications. Furthermore, the bioavailability of almost all of the PROTAC molecules are subject to food effects. There is a significant need for PROTACs compositions that have improved oral bioavailability, permit administering lower doses, that reduce absorption variations caused by food intake, and that reduce in vivo inter-subject absorption variations.

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Disclosed herein is a pharmaceutical composition, wherein the pharmaceutical composition comprises a) an amorphous solid dispersion (ASD) that comprises: i) a proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof; ii) a surfactant; iii) a hydrophilic polymer; iv) optionally an acid; and v) optionally an adsorbent, wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optional acid are present in the ADS in an amorphous state; and b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 2-fold compared to a bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof without being a part of an ASD, when said bioavailability is measured as total area under the curve (AUC) or as maximum plasma concentration (C) after oral administration to a subject in a fasted state. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 3, 4, or 5-fold compared to a bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof without being a part of an ASD, when said bioavailability is measured as total area under the curve (AUC) or as maximum plasma concentration (C) after oral administration to a subject in a fasted state. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 1.5-fold compared to a bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof without being a part of an ASD, when said bioavailability is measured as total area under the curve (AUC) or as maximum plasma concentration (C) after oral administration to a subject in a fed state. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 2, 2.5, or 3-fold compared to a bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof without being a part of an ASD, when said bioavailability is measured as total area under the curve (AUC) or as maximum plasma concentration (C) after oral administration to a subject in a fed state. In some embodiments, the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof is at least 5-fold compared to a bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof without being a part of an ASD. In some embodiments, the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof is at least 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold compared to a bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof without being a part of an ASD. In some embodiments, the corresponding composition comprises the PROTAC compound or the pharmaceutically acceptable salt thereof in an amorphous state. In some embodiments, the corresponding composition comprises the PROTAC compound or the pharmaceutically acceptable salt thereof in a crystalline form. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that does not vary more than 100%, 50%, 25%, when orally administered to a subject in a fed state compared to a fasted state, when said bioavailability is measured as total area under the curve (AUC) or as maximum plasma concentration (C) after oral administration to said subject. In some embodiments, the bioavailability is measured in a dog model in a fasted state or in a fed state. In some embodiments, the pharmaceutical composition is in a form of a tablet. In some embodiments, the pharmaceutical composition is in a form of a capsule. In some embodiments, the PROTAC compound is represented by the structure of Formula (I): A-L-B, wherein i) A is an E3 ubiquitin ligase binding moiety; ii) L is a linker; and iii) B is a moiety which binds to a target protein, wherein the target protein is degradable by an E3 ubiquitin ligase. In some embodiments, B is an androgen receptor (AR) binding moiety. In some embodiments, B is an estrogen receptor binding moiety. In some embodiments, the PROTAC compound is an androgen receptor PROTAC degrader. In some embodiments, the androgen receptor PROTAC degrader is ARV-110, or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the androgen receptor PROTAC degrader is represented by the structure of

or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the PROTAC compound is an estrogen receptor PROTAC degrader. In some embodiments, the estrogen receptor PROTAC degrader is ARV-471, or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the estrogen receptor PROTAC degrader is represented by the structure of

or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the PROTAC compound has a log P in octanol-water of at least 2.0. In some embodiments, the PROTAC compound has a log P in octanol-water of at least 2.0, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or at least 5. In some embodiments, the PROTAC compound or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 10% to 30% by weight. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 25 mg to about 250 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 10% to 60% by weight. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 15% to 55% by weight. In some embodiments, the surfactant comprises a non-ionic surfactant, an anionic surfactant, a phospholipid, or any combination thereof. In some embodiments, the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), a block copolymer of polyethylene glycol and polypropylene glycol, polysorbate, lecithin, polyethylene glycol castor oil, hydrogenated castor oil, sorbitan oleate, sodium dodecyl sulfate (SDS), polyvinylcaprolactame-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof. In some embodiments, the surfactant comprises tocopherol polyethylene glycol succinate (TPGS) or lecithin or a combination thereof. In some embodiments, the hydrophilic polymer is present in the pharmaceutical composition in an amount of about 10 mg to about 500 mg. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 1% to about 80% by weight. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 15% to about 50% by weight. In some embodiments, the hydrophilic polymer is vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), oligosaccharide, polysaccharide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC, or hypromellose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl beta cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin, hydropropylmethylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polymethacrylates, hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer (PVAc-PVCap-PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG), or a combination thereof. In some embodiments, polymethacrylates comprise Eudragit. In some embodiments, the hydrophilic polymer is vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or hydropropylmethylcellulose acetate succinate (HPMCAS). In some embodiments, the amorphous solid dispersion comprises an acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid. In some embodiments, the acid is tartaric acid, citric acid, or succinic acid. In some embodiments, a weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is from about 10:1 to about 1:10. In some embodiments, the ASD comprises an adsorbent. In some embodiments, the adsorbent is selected from the group consisting of silicon dioxide, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, crosslinked povidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, and also sugars or sugar alcohols such as sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide. In some embodiments, the adsorbent is present in the amorphous solid dispersion in an amount of about 10 to about 35% by weight. In some embodiments, a D50 value of particle diameter of the amorphous solid dispersion is from 1 μm to 1000 μm. In some embodiments, the D50 value is from about 1 μm to about 150 μm (e.g., 10 μm to 15 μm). In some embodiments, the amorphous solid dispersion further comprises an antioxidant (e.g., vitamin E). In some embodiments, the pharmaceutically acceptable carrier or excipient is free of organic acid. In some embodiments, the pharmaceutically acceptable carrier or excipient comprises an external acid that is not present in the amorphous solid dispersion. In some embodiments, the pharmaceutical composition is storage stable for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months at 5±3° C., wherein a storage stable pharmaceutical composition retains at least 90 wt % of the PROTAC compound or the pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical composition is storage stable for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months at 25±2° C., wherein a storage stable pharmaceutical composition retains at least 90 wt % of the PROTAC compound or the pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical composition is storage stable for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months at 40±2° C., wherein a storage stable pharmaceutical composition retains at least 90 wt % of the PROTAC compound or the pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical composition comprises a) an amorphous solid dispersion that comprises: (i) ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP, KT-413, or a pharmaceutically acceptable salt thereof in an amount of about 5% to about 50% by weight of the ASD; (ii) a surfactant in an amount of about 1% to about 60% by weight of the ASD, wherein the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, polyvinylcaprolactame-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; (iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, hydropropylmethylcellulose acetate succinate (HPMCAS), hydroxypropyl beta cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin, or a combination thereof; and (iv) optionally an acid in an amount of about 1% to about 50% by weight of the ASD; and b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises a) an amorphous solid dispersion that comprises: (i) an amorphous solid dispersion that comprises: ARV-110, ARV-471, or a pharmaceutically acceptable salt thereof in an amount of about 5% to about 50% by weight of the ASD; (ii) a surfactant in an amount of about 1% to about 50% by weight of the ASD, wherein the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, polyvinylcaprolactame-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; (iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, hydropropylmethylcellulose acetate succinate (HPMCAS), or hydroxypropyl beta cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin or a combination thereof; and (iv) optionally an acid in an amount of about 1% to about 50% by weight of the ASD, wherein the acid comprises tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof; and b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, a weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the surfactant is from about 1:0.5 to about 1:6, from about 1:0.8 to about 1:5, or from about 1:1 to about 1:3. In some embodiments, a weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is from about 1:0.5 to about 1:6, from about 1:0.8 to about 1:5, or from about 1:1 to about 1:3. In some embodiments, the ASD comprises ARV-110 or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 40% by weight of the ASD; a surfactant in an amount of about 5% to about 60% by weight of the ASD, wherein the surfactant is TPGS or lecithin or a combination thereof; a hydrophilic polymer in an amount of about 10% to about 60% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or HPMCAS or a combination thereof; and optionally an acid in an amount of about 5% to about 40% by weight of the ASD, wherein the acid is tartaric acid or citric acid. In some embodiments, the ASD comprises ARV-110 or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 35% by weight of the ASD; a surfactant in an amount of about 10% to about 50% by weight of the ASD, wherein the surfactant is TPGS or lecithin; a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or HPMCAS; and optionally an acid in an amount of about 10% to about 35% by weight of the ASD, wherein the acid is tartaric acid or citric acid. In some embodiments, the ARV-471 or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 40% by weight of the ASD; a surfactant in an amount of about 5% to about 60% by weight of the ASD, wherein the surfactant is TPGS or lecithin; a hydrophilic polymer in an amount of about 10% to about 60% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or HPMCAS; and optionally an acid in an amount of about 5% to about 40% by weight of the ASD, wherein the acid is tartaric acid or succinic acid. In some embodiments, the ASD comprises ARV-471 or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 35% by weight of the ASD; a surfactant in an amount of about 10% to about 50% by weight of the ASD, wherein the surfactant is TPGS or lecithin; a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylates (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or HPMCAS; and optionally an acid in an amount of about 10% to about 35% by weight of the ASD, wherein the acid is tartaric acid or succinic acid. In some embodiments, the pharmaceutical composition is formulated in a unit dosage form. In some embodiments, the unit dosage form comprises 30 to 300 mg of the PROTAC compound or a pharmaceutically acceptable salt thereof; 10 to 500 mg of the surfactant; 10 to 500 mg of the hydrophilic polymer; optionally an acid in an amount of 1 to 500 mg; and optionally an adsorbent in an amount of 1 to 500 mg; and optionally a pharmaceutically acceptable carrier or excipient.

Disclosed herein is an amorphous solid dispersion, wherein the amorphous solid dispersion comprises, (i) a proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof; (ii) a surfactant; (iii) a hydrophilic polymer; (iv) optionally an acid; and v. optionally an adsorbent, wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optional acid are present in the ASD in an amorphous state. In some embodiments, the PROTAC compound is ARV-110 or ARV-471.

Disclosed herein is a method of treating a disease or condition, comprising administering to a subject in need thereof the pharmaceutical composition or the amorphous solid dispersion described herein. In some embodiments, the pharmaceutical composition is administered with or without food. In some embodiments, the subject is in a fasted state. In some embodiments, the subject is in a fed state. In some embodiments, the disease or condition is cancer. In some cases, the cancer is the cancer is prostate cancer or breast cancer.

Disclosed herein is a method of ubiquitinating or degrading a target protein in a cell of a subject, comprising administering to a subject the pharmaceutical composition or the amorphous solid dispersion described herein.

Disclosed herein is a method for preparing an amorphous solid dispersion, comprising the steps: a) combining (i) proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof, (ii) a surfactant, (iii) a hydrophilic polymer, (iv) optionally an additive and (v) a solvent, thereby producing a liquid mixture or solution, and b) removing the solvent from said mixture, thereby producing an amorphous solid dispersion.

The present disclosure is generally directed to compositions comprising pharmaceutically active agents that are useful as therapeutics that alleviate, abate or eliminate one or more conditions in a subject in need thereof, as further described herein. In particular, described herein are pharmaceutical compositions, their manufacturing process and use, where the pharmaceutical compositions comprise a PROTAC, a hydrophilic polymer, and a surfactant in a combination such that the PROTAC has improved bioavailability compared to the PROTAC alone. In some embodiments, the PROTAC, a hydrophilic polymer, one or more surfactant, and optionally an acid, are in an amorphous solid dispersion. The presently disclosed pharmaceutical compositions comprising amorphous solid dispersions that comprise PROTACs and suitable excipients or carriers provide better bioavailability and reduced food-effects than the crystalline form or other conventional dosage forms of such PROTACs. In some embodiments, the conventional dosage forms of PROTACs include dosage forms comprising PROTACs in a crystalline form. In some embodiments, the conventional dosage forms of PROTACs include dosage forms comprising PROTACs in an amorphous state without being a part of an ASD. In some embodiments, the conventional dosage forms comprise the PROTAC in a crystalline form. In some embodiments, the conventional dosage forms comprise the PROTAC in an amorphous state. In some embodiments, the conventional dosage forms comprise PROTACs compound filled in a capsule. In some embodiments, the conventional dosage forms do not comprise an ASD. In some embodiments, the ASD comprises a PROTAC, a surfactant (e.g., lecithin or TPGS), and a hydrophilic polymer.

The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:

Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers +/−10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

The singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “the surfactant” includes reference to one or more specific surfactants, reference to “an antioxidant” includes reference to one or more of such additives.

The term “subject” as used herein refers to a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee or baboon).

“AUC” or “AUC” as used herein refers to the area under the plasma drug concentration-versus-time curve extrapolated from zero time to infinity. “AUC” as used herein refers to the area under the curve from the time of dosing to the time of the last measurable concentration. “C” as used herein refers to the highest drug concentration observed in plasma following an extravascular dose of drug. “T” as used herein refers to the time after administration of a drug when the maximum plasma concentration is reached. In some cases, the AUC, AUC, or Ccan be used to measure bioavailability of an API described herein (e.g., a PROTAC). In some cases, improvements or differences in bioavailability of the API in various oral compositions (e.g., the ASD compositions described herein) can be evaluated by AUC, AUC, or C. In some cases, the bioavailability of the API is evaluated in a subject in fed condition or in fasted condition. In some cases, an absolute bioavailability of the API is measured via plasma concentrations of the API achieved by i.v. injection.

“D10,” “D50,” and “D90” are used herein to describe a particle size distribution. The “D10” as used herein refers to the diameter that has ten percent of the total mass of the particles smaller and ninety percent larger. The “D50” as used herein refers to the median diameter where fifty percent of the total mass of particles are larger and 50% are smaller. The “D90” defines the diameter where ninety percent of the mass distribution has a smaller particle diameter and ten percent has a larger particle diameter.

In some embodiments, an error-band is included. The term “total error band” is used herein to specify all sources of including sampling and sample preparation calculated at a 95% confidence level. An example is: D50 100 μm with a total error band of +/−5% on size. Other statistics are sometimes used to describe a particle size distribution. The most common calculations are standard deviation and variance. The standard deviation (St Dev.). The standard deviation specification defines the diameter where approximately 68.27% of the total population lies within +/−1 St Dev, and 95.45% lies within +/−2 St Dev.

“Effective amount,” and “sufficient amount” may be used interchangeably, and refer to an amount of a substance that is sufficient to achieve an intended purpose or objective.

A “therapeutically effective amount” when used in connection with a pharmaceutical composition described herein is an amount of one or more pharmaceutically active agent(s) sufficient to produce a therapeutic result in a subject in need thereof.

“Therapeutically equivalent” when used in connection with a pharmaceutical composition described herein refers to an amount or quantity of a pharmaceutically acceptable salt or ester of a pharmaceutically active agent that is equivalent to the therapeutically effective amount of the free base or alcohol of the pharmaceutically active agent.

The prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.

“Amino” refers to the —NHradical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NOradical.

“Methoxyl” refers to the —O-Me radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NHradical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Hydroxyamino” refers to the —NH—OH radical.

“Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification, an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

“Acyl-sulfonamide” refers to a monovalent radical where the carbon atom of a carbonyl is bound to a sulfonamide group. Exemplary acyl-sulfonamides include —C(O)NRS(O)R, —C(O)NRS(O)N(R), —NRS(O)C(O)R, —NRS(O)C(O)N(R), —C(O)NRS(O)C(O)N(R), —NRS(O)NRC(O)N(R), —C(O)NRS(O)NRC(O)N(R), and —C(O)S(O)N(R), where each Ris independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C-Calkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C-Calkyl, a C-Calkyl, a C-Calkyl, a C-Calkyl, a C-Calkyl, a C-Calkyl, a C-Calkyl, a C-Calkyl, a C-Calkyl, or a Calkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, —NO, or —C≡CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

“Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (—CH═CH), 1-propenyl (—CHCH═CH), isopropenyl [—C(CH)═CH], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C-Calkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C-Calkenyl, a C-Calkenyl, a C-Calkenyl, a C-Calkenyl, a C-Calkenyl, a C-Calkenyl, a C-Calkenyl, a C-Calkenyl, or a Calkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C-Calkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C-Calkynyl, a C-Calkynyl, a C-Calkynyl, a C-Calkynyl, a C-Calkynyl, a C-Calkynyl, a C-Calkynyl, a C-Calkynyl, or a Calkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is —CH—, —CHCH—, or —CHCHCH—. In some embodiments, the alkylene is —CH—. In some embodiments, the alkylene is —CHCH—. In some embodiments, the alkylene is —CHCHCH—.

“Alkylamino” refers to a radical of the formula —N(R)where Ris an alkyl radical as defined, or two R, taken together with the nitrogen atom, can form a substituted or unsubstituted C-Cheterocyloalkyl ring such as:

Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, the alkylamino is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula —ORwhere Ris an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, the alkoxy is optionally substituted with halogen.